Cancer encompasses many disease states generally characterized by abnormally proliferating cells. Cancers are collectively the second leading cause of death in the United States today. While various conventional regimes to treat the myriad of cancers which affect the population including radiation, chemotherapy and surgery find limited success, no fundamental trait or characteristic has been associated with the wide array of cancers known today which has permitted an effective uniform and successful response to this disease state.
Gastrointestinal cancers, for example, represent a class of neoplasias affecting the population at rates which evidence little or no success by conventional treatment regimes. Some malignancies in this class have virtually little hope of successful treatment. Notably, for example, pancreatic cancer is a fatal malignancy occurring in over 28,000 Americans each year, and ranks as the fourth most common cause of cancer-related mortality in the United States. For reasons that are not entirely understood, the incidence of pancreatic cancer has tripled over the past four decades. The median of survival after diagnosis is 3-6 months, with a five-year survival rate of approximately 2%. In spite of treatment efforts including surgery, radiation and chemotherapy the survival rate has not changed significantly for decades.
Furthermore, approximately 160,000 new cases of colon and rectal cancer occur each year in the United States, and about 65,000 deaths are attributed annually to this disease. It is the second leading cause of cancer mortality in the United States. Despite its frequent occurrence and intense basic and clinical science research, the incidence and mortality rate of this disease have remained relatively stable over the past few decades.
Recently a number of growth factors have been identified to be associated with, and which may be important in, carcinogenesis, including neoplasias of the gastrointestinal tract. It has been shown, for example, that alteration-in these growth factors and/or their receptors could lead to disease states such as cancer, and thus may offer clues in the treatment of neoplasias. However, the data reflected in the literature extant evidences various circumstances which are entirely conflicting, evidencing both inhibition and acceleration of cell growth.
One group of peptidesxe2x80x94the endogenous opioidsxe2x80x94appears to be important in the growth of normal, neoplastic, renewing, and healing tissues, as well as in prokaryotes and other eukaryotic organisms. Most notably, the pentapeptide, [Met5]-enkephalin, has been identified as an endogenous opioid directly involved in growth processes, serving as a negative regulator in a wide variety of cells and tissues. Cell proliferation, as well as cell migration, differentiation, and survival, are influenced by this growth peptide. In view of a direct influence on the growth of neural and non-neural cells and tissues, and its non-modulatory action, [Met5]-enkephalin has been termed opioid growth factor (OGF). [Met5]-enkephalin interacts with xcex4 and xcexc opioid receptors of neuronal cells when serving as a neurotransmitter.
In earlier work, the present inventors identified certain exogenous opioid antagonists including naloxone and naltrexone as effecting growth regulation in a wide array of cellular sources. For example, experiments utilizing a murine model of neuroblastoma and naltrexone, have shown that the effects of these antagonists depend on the duration of receptor blockade. Thus, in A/Jax mice inoculated with neuroblastoma, chronic receptor blockade using either a single drug concentration of 10 mg/kg per day or repeated injections of a low drug dosage of 0.1 mg/kg given 4 times daily accelerated the course of tumorigenesis and shortened survival. These data indicated that opioids are negative regulators of growth. A/Jax mice inoculated with neuroblastoma cells and receiving a single daily injection of 0.1 mg/kg naltrexone exhibited an antitumor effect (e.g. decreased tumor incidence). It is now understood that this drug dosage blocks the opioid receptors for 4-6 h/day, thereby producing a subsequent period of elevated enkephalin levels and/or receptor number and leading to a xe2x80x9csupersensitivityxe2x80x9d to endogenous enkephalins. Thus, there is a sufficient interval each day for the interaction of opioids and/or receptors to retard tumorigenic events by way of a supersensitive response.
While the prior art has reported various observations and interactions of endogenous opioids and certain exogenous opioid antagonists in the context of cell growth, prior investigations fail to evidence sufficient relationship between such opioids and/or antagonists to permit uniform and effective treatment of a wide array of cancers including particularly, for example, gastrointestinal cancers. Moreover, the inconsistencies which have been characteristic of the prior art have frustrated the determination of meaningful broad based regimes utilizing these growth factors and/or the interaction with their receptors.
It has presently been discovered that endogenous [Met5]-enkephalin interfaces with an opioid receptor (xcex6) to modulate cellular growth and particularly the growth of cancerous tumors which surprisingly are uniformly characterized by the presence of such receptors. Furthermore, in accordance with the present invention, it has been demonstrated that tumor growth can be controlled, e.g. inhibited, by the manipulation of the interaction between the endogenous opioid, [Met5]-enkephalin and this newly discovered opioid receptor named the zeta (xcex6) receptor. Identification of this receptor in growing cancer cells permits an understanding which, for the first time, facilitates meaningful broad based prevention, treatment and arrest of cancer.
It is an object of the present invention to provide methods for the prevention, treatment and arrest of cancers which are characterized by the presence of zeta receptors.
It is another object of the present invention to temporarily accelerate the growth of cancers which are characterized by the presence of a zeta receptor in order to treat such proliferating cells with chemotherapeutic agents which are efficacious against the cell proliferation of cancer.
These and other objects of the present invention are achieved by the administration of, or treatment with the opioid antagonist naloxone or naltrexone (or mixtures thereof) in an amount sufficient to effect the intermittent blockade of the zeta receptor present in the cancer cell (and surrounding tissue) thereby producing a subsequent period of elevated endogenous enkephalin levels or receptor numbers to inhibit, arrest and even prevent tumor growth. Alternatively, exogenous [Met5]-enkephalin can be administered in amounts sufficient to occupy the zeta receptors of the tumor cell and thereby effect inhibition, arrest and even prevention of cancer cell growth.
Tumor cell proliferation, e.g. for targeting by chemotherapeutic agents such as cis-platin and adriamycin can be effected by either continuous blockade of the zeta receptor or other approaches which block endogenous [Met5]-enkephalin interaction at the zeta receptor site.